{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:52:30Z","timestamp":1786121550393,"version":"build-2736575974"},"reference-count":32,"publisher":"Wiley","issue":"29","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["112\u20102221\u2010E\u2010038\u2010002\u2010MY3"],"award-info":[{"award-number":["112\u20102221\u2010E\u2010038\u2010002\u2010MY3"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020595","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["114\u20102628\u2010E\u2010038\u2010001\u2010MY3"],"award-info":[{"award-number":["114\u20102628\u2010E\u2010038\u2010001\u2010MY3"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004737","name":"National Health Research Institutes","doi-asserted-by":"publisher","award":["NHRI\u2010EX115\u201011323EI"],"award-info":[{"award-number":["NHRI\u2010EX115\u201011323EI"]}],"id":[{"id":"10.13039\/501100004737","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010613","name":"Taipei Medical University Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010613","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Adv Healthcare Materials"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Osteoarthritis (OA) is driven by intertwined pathological processes, including chronic inflammation, oxidative stress, immune imbalance, hypoxia, and aberrant angiogenesis, while current noninvasive therapies remain limited by insufficient deep\u2010joint delivery and poor multidimensional regulation. Here, an extracellular vesicle (EV)\u2010centered, near\u2010infrared (NIR)\u2010responsive transdermal platform is developed to address these challenges. Apple\u2010derived extracellular vesicles (AEVs) are used as intrinsically bioactive nanocarriers to co\u2010deliver berberine (BBR) and piperine (PIP), and are integrated into a biocompatible dextran\/alginate hydrogel containing graphene oxide (GO). Under NIR stimulation, GO provides on\u2010demand energy conversion that supports mild hyperthermia\u2010assisted barrier loosening together with potential photo\u2010redox\u2010associated microenvironment modulation, thereby enhancing local therapeutic availability while maintaining a safe thermal window. In vivo assessment of TRPV1 expression and tight\u2010junction\u2010related responses provides supportive indication for transport\u2010associated modulation, whereas ex vivo diffusion findings are interpreted as barrier\u2010level permeation evidence rather than direct confirmation of in vivo mechanisms. In an OA rat model, the NIR\u2010activated platform is associated with reduced joint inflammation and edema, attenuated oxidative stress, improved macrophage polarization toward an anti\u2010inflammatory phenotype, enhanced gait\u2010related joint function, and preservation of cartilage structure. This study establishes a noninvasive, stimulus\u2010responsive transdermal strategy for localized and multifaceted OA microenvironment modulation.<\/jats:p>","DOI":"10.1002\/adhm.71330","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T03:50:47Z","timestamp":1784173847000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HOF\u2010Stabilized Apple EV Nanocargo in an NIR\u2010Responsive Hydrogel Enables On\u2010Demand Therapeutic Modulation for Transdermal Deep\u2010Joint Osteoarthritis Therapy"],"prefix":"10.1002","volume":"15","author":[{"given":"Yu\u2010Wen","family":"Tseng","sequence":"first","affiliation":[{"name":"Graduate Institute of Biomedical Materials and Tissue Engineering International Ph.D. Program in Biomedical Engineering College of Biomedical Engineering Taipei Medical University  New Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei\u2010Wei","family":"Weng","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Shuang Ho Hospital Taipei Medical University  New Taipei City Taiwan"},{"name":"Department of Orthopedics School of Medicine College of Medicine Taipei Medical University  Taipei City Taiwan"},{"name":"Research Center of Biomedical Devices Taipei Medical University  Taipei Taiwan"},{"name":"Graduate Institute of Nanomedicine and Medical Engineering College of Biomedical Engineering Taipei Medical University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsien\u2010Tsung","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Orthopedics Taipei Medical University Hospital  Taipei Taiwan"},{"name":"Department of Orthopedics School of Medicine College of Medicine Taipei Medical University  Taipei Taiwan"},{"name":"International Ph.D. Program in Cell Therapy and Regenerative Medicine College of Medicine Taipei Medical University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiunn\u2010Horng","family":"Kang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Nanomedicine and Medical Engineering College of Biomedical Engineering Taipei Medical University  Taipei Taiwan"},{"name":"Department of Physical Medicine and Rehabilitation Taipei Medical University Hospital  Taipei Taiwan"},{"name":"Department of Physical Medicine and Rehabilitation School of Medicine College of Medicine Taipei Medical University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lekha","family":"Rethi","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Shuang Ho Hospital Taipei Medical University  New Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lekshmi","family":"Rethi","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Materials and Tissue Engineering International Ph.D. Program in Biomedical Engineering College of Biomedical Engineering Taipei Medical University  New Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan\u2010Ting","family":"Chen","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Materials and Tissue Engineering International Ph.D. Program in Biomedical Engineering College of Biomedical Engineering Taipei Medical University  New Taipei City Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hieu Trung","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Trauma Faculty of Medicine University of Medicine and Pharmacy at Ho Chi Minh City  Ho Chi Minh City Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao\u2010Tung","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Tri\u2010Service General Hospital National Defense Medical University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew E.\u2010Y.","family":"Chuang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Biomedical Materials and Tissue Engineering International Ph.D. Program in Biomedical Engineering College of Biomedical Engineering Taipei Medical University  New Taipei City Taiwan"},{"name":"Cell Physiology and Molecular Image Research Center Taipei Medical University\u2010Wan Fang Hospital  Taipei Taiwan"},{"name":"Precision Medicine and Translational Cancer Research Center Taipei Medical University Hospital  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41584\u2010021\u201000673\u20104"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201038597\u20100"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2023.03.030"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5b08057"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2020.120155"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cej.2021.130066"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202204881"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202203240"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.8b10904"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2022.08.054"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202207490"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2022.121530"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsami.1c17420"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abf6654"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adi5501"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.4274\/tji.galenos.2024.20082"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13346\u2010023\u201001473\u2010x"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951\u2010023\u201002068\u2010x"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.201101414"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsbiomaterials.2c01551"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202402864"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.renene.2022.06.049"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.memsci.2022.121118"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1039\/C5NR06726J"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpx.2024.100311"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.3109\/01480545.2011.589437"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcis.2025.01.202"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010025\u201005137\u20103"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13104\u2010015\u20101618\u20106"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40828\u2010018\u20100076\u2010x"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2024.06.007"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2023.06.012"}],"container-title":["Advanced Healthcare Materials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/adhm.71330","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/adhm.71330","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/adhm.71330","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T05:42:04Z","timestamp":1786081324000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/adhm.71330"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,15]]},"references-count":32,"journal-issue":{"issue":"29","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/adhm.71330"],"URL":"https:\/\/doi.org\/10.1002\/adhm.71330","archive":["Portico"],"relation":{},"ISSN":["2192-2640","2192-2659"],"issn-type":[{"value":"2192-2640","type":"print"},{"value":"2192-2659","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,15]]},"assertion":[{"value":"2026-02-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e71330"}}